title: Synthesis of alkenyldiarylmethanes (ADAMs) containing benzo[d]isoxazole and oxazolidin-2-one rings, a new series of potent non-nucleoside HIV-1 reverse transcriptase inhibitors.
abstract: As a continuation of efforts to replace the metabolically labile methyl esters of lead alkenyldiarylmethanes (ADAMs) with stable bioisosteres, compounds bearing benzo[d]isoxazole and oxazolidine-2-one rings were designed and evaluated as a new series of potent HIV-1 non-nucleoside reverse transcriptase inhibitors with anti-HIV activity. All of the resulting ADAMs were found to inhibit HIV-1 RT with poly(rC) x oligo(dG) as the template primer. The most promising compound in this series was ADAM 3, with EC(50) values of 40 nM (vs HIV-1(RF)) and 20 nM (vs HIV-1(IIIB)). Compound 3 also inhibited HIV-1 reverse transcriptase with an IC(50) of 0.91 microM. ADAM 4 has an antiviral EC(50) of 0.6 microM in CEM-SS cells and a plasma half-life of 51.4 min.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and the Purdue Cancer Center, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Bo-Liang
authors.initials: BL
authors.lastname: Deng
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhao
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Hartman
authors.forename: Karen
authors.initials: K
authors.lastname: Watson
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D007555:Isoxazoles; D023303:Oxazolidinones; D018894:Reverse Transcriptase Inhibitors